Endogenous coagulation activator compounds —use in exploring endogenous coagulation

Abstract

The invention concerns contact activators for the endogenous coagulation pathway and their use in exploring coagulation anomalies. The activators of the invention are derivatives of gallic acid, preferably polyethylene glycol gallates.

1. A composition, which comprises a mixture of at least two different compounds with formula: 
       
         
           
           
               
               
           
         
       
       wherein group A and group R are identical or different on said two different compounds, and wherein A is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       where M +  is a cation, q is 1 or 2 and p×q=2; and wherein R is selected from the group consisting of —[O—(CH 2 ) m]n —OH, where m is equal to 2, 3, 4 or 5 and n is a whole number between 1 and 170, —[NH—(CH 2 ) m]n —NH 2 , where m is equal to 2, 3, 4 or 5 and n is a whole number between 1 and 170, and a peptide containing between 1 and 12 amino acids, the composition comprising at least a compound wherein A is 
       
         
           
           
               
               
           
         
       
       where M +  is a cation, q is 1 or 2 and pxq is 2. 
     
     
       2. The composition according to  claim 1 , which comprises a mixture of compounds 
       
         
           
           
               
               
           
         
       
       in which M +  is a cation, q is 1 or 2 and p×q=2, having the acidic and basic forms of oxidized ethylene glycol gallate (EGGox). 
     
     
       3. The composition according to  claim 1 , which comprises different forms of ethylene glycol gallate produced by the keto-enol equilibrium and having the formula: 
       
         
           
           
               
               
           
         
       
       in which A is selected from group consisting of 
       
         
           
           
               
               
           
         
       
       M +  is a cation, q is 1 or 2 and p×q=2; and wherein R is O—CH 2 —CH 2 —OH. 
     
     
       4. The composition according to  claim 1 , which comprises basic EGGox with the formula: 
       
         
           
           
               
               
           
         
       
       wherein M +  is a cation, q is 1 or 2 and p×q=2. 
     
     
       5. The composition according to  claim 1 , which further comprises, in a stabilized equilibrium, compounds with formulae 
       
         
           
           
               
               
           
         
       
     
     
       6. The composition according to  claim 1 , which contains a mixture of compounds with formulae 
       
         
           
           
               
               
           
         
       
       which pH is in the range of 7.6 to 7.8. 
     
     
       7. The composition according to  claim 1 , which activates endogenous coagulation in contact with a plasma sample, and which further comprises a buffer selected from from (N-morpholino) propanesulphonic acid (MOPS) or N-tris (hydroxymethyl) methyl-glycine (TRICINE). 
     
     
       8. The composition according to  claim 7 , wherein the concentration of said compounds is sufficient to activate endogenous coagulation in a plasma sample when contacted with said sample. 
     
     
       9. The composition according to  claim 1 , wherein the cation is a metal cation. 
     
     
       10. The compound according to  claim 9 , wherein the metal cation is selected from the group of Mn 2+ , Cu 2+ or Co 2+ . 
     
     
       11. A reagent system for use in vitro examination of endogenous coagulation, comprising a composition according to  claim 1 , under conditions such that it constitutes a compound with formula: 
       
         
           
           
               
               
           
         
       
       wherein M +  is a cation, q is 1 or 2 and p×q=2; and wherein R is selected from the group consisting of —[—(CH 2 ) m]n —OH, where m is equal to 2, 3, 4 or 5 and n is a whole number between 1 and 170, —[NH—(CH 2 ) m]n—NH   2 , where m is equal to 2, 3, 4 or 5 and n is a whole number between 1 and 170, and a peptide containing between 1 and 10 amino acids. 
     
     
       12. The composition according to  claim 1 , or a reagent system according to  claim 11 , wherein the ethylene glycol gallate concentration is in the range 100 μM to 1000 μM. 
     
     
       13. The composition according to  claim 1 , further comprising a substituted poly-aminoacid constituent. 
     
     
       14. A process for exploring coagulation by an endogenous pathway comprising measuring an activated thromboplastin time in a blood or a plasma sample using the composition of  claim 1 . 
     
     
       15. A process for exploring coagulation by an endogenous pathway comprising measuring an activated thromboplastin time in a blood or a plasma sample using the composition of  claim 2 . 
     
     
       16. A process for exploring coagulation by an endogenous pathway comprising measuring an activated thromboplastin time in a blood or a plasma sample using the composition of  claim 13 . 
     
     
       17. The composition according to  claim 1 , wherein n is a whole number between 1 and 50, 1 and 30 or 1 and 20.